The present invention relates to new nitromethyl ketones, to their preparation and to their use as medicaments, especially in the treatment or prevention of the complications of diabetes.
Diabetes is characterized by a high concentration of glucose in the blood. This glucose is normally metabolized by the enzyme hexokinase during the first stage of glycolysis, leading to the degradation into pyruvate. When the glucose concentration is too high, hexokinase becomes saturated and a second pathway for glucose metabolism comes into play. It is the polyol pathway which involves two enzymes successively: aldose reductase which converts glucose to sorbitol arid sorbitol dehydrogenase which converts sorbitol to fructose. In the event of diabetes, the excess glucose accelerates the formation of sorbitol which tends to accumulate. This results in serious metabolic disturbances, such as for example an increase in osmotic pressure which can lead to tissue degeneration. Aldose reductase inhibitors are therefore useful for treating or preventing certain complications induced by diabetes.
Numerous products are described in the literature, such as aldose reductase inhibitors which are active in vitro and in vivo.
They are mainly derivatives of hydantoins, of succinimides and of acetic acids and more recently derivatives of sulfonylnitromethanes.
The present invention relates to nitromethyl ketone derivatives and their addition salts with physiologically acceptable bases, corresponding to the general formula (I): 
in which
A represents C6-C10 aryl or an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N;
X represents halogen, cyano, C1-C7 alkyl, trifluoromethyl, C2-C7 alkoxy or trifluoromethoxy;
R1 and R2, which are identical or different, represent a hydrogen atom, a C1-C7 alkyl group, a C3-C12 cycloalkyl group, a trifluoromethyl group, a C1-C7 alkoxy group or R1 or R2 together form an alkylene chain of the xe2x80x94(CH2)rxe2x80x94 type, where r is chosen from 2, 3 and 4;
is chosen from 0, 1, 2, 3, 4 and 5;
Z represents a bond, the divalent radical xe2x80x94COxe2x80x94NHxe2x80x94 in which the carbonyl function is linked to R3, the divalent radical xe2x80x94SO2xe2x80x94NHxe2x80x94 in which the sulfonyl function is linked to R3, a C2-C7 alkenylene radical, a sulfur atom, the sulfinyl group or a sulfonyl group;
R3 represents a hydrogen atom; a halogen atom; a tri-(C1-C7-alkyl)silyl group; a C1-C7 alkyl group optionally substituted with one or more identical or different Y radicals; a C6-C10 aryl group optionally substituted with one or more identical or different Y radicals;, a C6-C10 aryloxy group optionally substituted with one or more identical or different Y radicals; a C3-C12 cycloalkyl group optionally substituted with one or more identical or different Y radicals; an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, S and N, the heterocycle being optionally substituted with one or more identical or different Y radicals, or R3 represents indanyl, 1,3-dihydro-1,3-dioxo-2H-iso-indol-2-yl, 1,3-benzodioxolyl, 2-oxopiperidinyl or 2-[(4-nitromethylcarbonyl-3-chlorophenyl)amino-carbonyl]-1-(phenyl)ethyl;
Y represents a halogen atom, C1-C7 alkyl, C1-C7 alkoxy, trifluoromethyl, carboxy, carbamoyl, (C1-C7)alkylcarbamoyl, di-(C1-C7)alkylcarbamoyl, C1-C7 alkoxycarbonyl, amino, C1-C7-alkylamino, di-(C1-C7)-alkylamino, nitro, cyano, hydroxy, trifluoromethoxy, C3-C12 cycloalkyl, sulfo, C1-C7 alkylthio, C1-C7 alkylsulfinyl, C1-C7 alkylsulfonyl, C2-C8 alkylcarbonyl, C2-C8 alkylthiocarbonyl, C2-C8 alkylcarbonylamino, or C6-C10 aryl;
E represents a divalent radical chosen from:
(i) xe2x80x94COxe2x80x94NR4xe2x80x94 in which the carbonyl group is linked to xe2x80x94(CR1R2)pxe2x80x94 and R4 represents the radical xe2x80x94(CH2)qxe2x80x94R5 where q is chosen from 0 and 1; and where R5 represents a hydrogen atom; a C1-C7 alkyl group; a C6-C10 aryl group or an optionally aromatic three- to ten-membered heterocycle in which one to four ring atoms are identical or different heteroatoms chosen from O, N and S; or R5 and R3 together form a bond;
(ii) xe2x80x94SO2xe2x80x94NR4xe2x80x94 in which the sulfonyl group is linked to xe2x80x94(CR1R2)pxe2x80x94 and R4 is as defined above;
(iii) xe2x80x94NR4xe2x80x94 in which R4 is as defined above;
(iv) xe2x80x94CHxe2x95x90Nxe2x80x94 in which the nitrogen atom is linked to A; and
(v) an oxygen atom;
n represents 0 or 1; on the condition that xe2x80x94A(X)xe2x80x94(E)nxe2x80x94(CR1R2)pxe2x80x94Zxe2x80x94R3 does not represent halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl, 4-ethoxy-2-methylaminophenyl, methylindolyl, dimethylindolyl, 2-hydroxyphenyl substituted with a group X, 2-methoxyphenyl substituted with a group X and optionally substituted 2-fluorophenyl as defined above, and on the condition that when A represents pyridyl, X represents methyl and n is equal to 1, E does not represent xe2x80x94NR4xe2x80x94.
These compounds are inhibitors of the enzyme aldose reductase and may be used in the treatment or prevention of the complications of diabetes: neurological, peripheral and autonomous complications, renal complications and ocular complications such as cataract and retinopathy.
The physiologically acceptable salts of the compounds of formula (I) comprise the salts formed with metals (such as sodium, potassium, calcium, magnesium, aluminum), or with bases such as ammonium hydroxide or substituted amines (such as diethylamine, triethylamine, piperidine, piperazine, morpholine) or basic amino acids (such as lysine, arginine) or with osamines (such as meglumine) or with amino alcohols (such as 3-aminobutanol, 2-aminoethanol).
The term xe2x80x9carylxe2x80x9d represents an aromatic mono- or bicyclic group comprising 6 to 10 carbon atoms, such as phenyl or naphthyl.
The term xe2x80x9cheterocyclexe2x80x9d denotes a mono- or bicyclic ring with an aromatic character or otherwise, comprising 3 to 10 ring atoms of which 1 to 4 are identical or different heteroatoms chosen from oxygen, sulfur and nitrogen, such as for example, the aziridinyl, oxiranyl, oxazolyl, furyl, tetrahydrofuranyl, thienyl, imidazolyl, pyridyl, pyrazinyl, benzothienyl, benzopyranyl, benzofuryl, benzothiazolyl, pyrimidinyl, pyridazinyl, piperidinyl, quinolyl, tetrahydroquinolyl, tetrazolyl, phthalazinyl, purinyl, indolyl, chromenyl, chromanyl, isochromanyl and pyrrolyl.
The term xe2x80x9ccycloalkylxe2x80x9d denotes saturated hydrocarbon groups containing 3 to 12 carbon atoms, preferably 3 to 8, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecenyl and cyclododecyl.
The term xe2x80x9chalogenxe2x80x9d represents a fluorine, chlorine, bromine or iodine atom.
The term xe2x80x9calkylxe2x80x9d denotes a linear or branched hydrocarbon radical such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, isobutyl, pentyl, hexyl, heptyl.
The term xe2x80x9calkoxyxe2x80x9d denotes an alkyl group linked to an oxygen atom. Examples thereof are the methoxy, ethoxy, isopropyloxy, butoxy, hexyloxy radicals.
Likewise, xe2x80x9caryloxyxe2x80x9d denotes an aryl radical as defined above linked to an oxygen atom, such as phenoxy and naphthyloxy.
According to the invention, xe2x80x9calkenylenexe2x80x9d radical is understood to mean, moreover, a divalent hydrocarbon radical, carrying one or more ethylenic double bonds such as, for example, xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 or CHxe2x95x90CHxe2x80x94CHxe2x95x90CHxe2x80x94.
xe2x80x9cCarbamoylxe2x80x9d radical denotes the monovalent radical of formula xe2x80x94COxe2x80x94NH2. The radical xe2x80x9c(C1-C7)alkylcarbamoylxe2x80x9d denotes a carbamoyl radical substituted with. a C1-C7 alkyl group on the nitrogen atom and the radical xe2x80x9cdi-(C1-C7)alkylcarbamoylxe2x80x9d denotes a carbamoyl radical substituted on the nitrogen atom with two C1-C7 alkyl groups.
The radical xe2x80x9c(C1-C7)alkoxycarbonylxe2x80x9d denotes a radical Rxe2x80x94Oxe2x80x94COxe2x80x94 in which R represents a C1-C7 alkyl group.
The radical xe2x80x9c(C1-C7)alkylaminoxe2x80x9d denotes an amino group substituted on the nitrogen atom with a (C1-C7)alkyl radical and the radical xe2x80x9cdi-(C1-C7)alkylaminoxe2x80x9d denotes an amino group substituted on the nitrogen atom with two (C1-C7)alkyl radicals.
The terms xe2x80x9calkylthioxe2x80x9d, xe2x80x9calkylsulfinylxe2x80x9d and xe2x80x9calkylsulfonylxe2x80x9d represent an alkyl group linked to a sulfur atom which is respectively nonoxidized, mono-oxidized or di-oxidized, such as methylthio, methylsulfinyl or methylsulfonyl.
Some compounds related to this type are known. For example, DE 2,415,350 describes antiallergic compounds of formula: 
in which R1, R2, R3, R4, which are identical or different, may represent a hydrogen or halogen atom, an alkyl, alkoxy, aryl or arylalkyl group, a heterocycle or, two by two, a carbocycle or a heterocycle.
In patent DE 2,741,011, antihistaminic-antiallergic compounds are described, which are of the formula: 
in which R0 represents a hydrogen atom, a (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-(C1-C2)alkyl, (C3-C6)alkenyl or (C3-C6)alkynyl group or a radical of formula 
Nitromethyl ketone derivatives attached to polysubstituted naphthyridines and quinolones are described in patent EP 574 231 for an antibiotic activity.
Other nitromethyl ketone derivatives have been described in the literature, for example as synthesis intermediates, but the prior art does not refer at all to a potential therapeutic use of these compounds. There may be mentioned for example J. SETER, Israel J. Chem (1966) 4, 7-22 or BAKER D. C. and PUTT S. R., Synthesis (1978) 678-9 or FIELD G. F. and ZALLY W. J., Synthesis (1979) 295-6 or HAMADA Yasumasa et al., Chem. Pharm. Bull (1981) 29, 259-61.
The known nitromethyl ketone derivatives do not correspond to the formula (I) of the compounds of the invention; moreover, none of these compounds is described as having any inhibitory activity towards aldose reductase.
Preferred compounds of the invention are those for which, in the formula (I):
A represents phenyl, n and p represent 0, Z represents a bond and R3 represents a hydrogen atom, or
A represents phenyl, n represents 1 and E represents xe2x80x94COxe2x80x94NR4xe2x80x94, and more particularly those for which p represents 1, R1 and R2 represent a hydrogen atom and Z represents a bond; or
A represents phenyl, n represents 1, E represents xe2x80x94SO2xe2x80x94NR4xe2x80x94; or
A represents phenyl, n is equal to 1, E represents xe2x80x94COxe2x80x94NR4xe2x80x94, p is equal to 0 and Z represents xe2x80x94SO2xe2x80x94NHxe2x80x94; or
A represents an aromatic heterocycle such as benzothienyl or thienyl; or
A represents naphthyl; or
n represents 1 and E represents an oxygen atom.
Another group of preferred compounds consists of the compounds of formula: 
in which
A represents phenyl, naphthyl, benzothienyl or thienyl;
X represents halogen, cyano, C1-C7 alkyl, trifluoromethyl, C2-C7 alkoxy or trifluoromethoxy;
R1 and R2 represent a hydrogen atom, or R1 and R2 together form an alkylene chain of the xe2x80x94(CH2)rxe2x80x94 type, where r is chosen from 2, 3 and 4;
p is chosen from 0, 1, 2 and 3;
Z represents a bond, the divalent radical xe2x80x94COxe2x80x94NHxe2x80x94 in which the carbonyl function is linked to R3 or the divalent radical xe2x80x94SO2xe2x80x94NHxe2x80x94 in which the sulfonyl function is linked to R3;
R3 represents a hydrogen atom, C1-C7 alkyl optionally substituted with one or more identical or different Y radicals; phenyl optionally substituted with one or more identical or different Y radicals; phenoxy optionally substituted with one or more identical or different Y radicals; C3-C12 cycloalkyl optionally substituted with one or more identical or different Y radicals; benzothienyl; benzofuryl; or R3 represents 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl or 2-oxo-piperidinyl;
Y represents a halogen atom, C1-C7 alkoxy, trifluoromethyl, carboxy, trifluoromethoxy or phenyl;
E represents a divalent radical chosen from:
(i) xe2x80x94COxe2x80x94NR4 in which the carbonyl group is linked to xe2x80x94(CR1R2)pxe2x80x94 and R4 represents the radical (CH2)qxe2x80x94R5 where q is chosen from 0 and 1, and where R5 represents a hydrogen atom, a C1-C7 alkyl group or a phenyl group;
(ii) xe2x80x94SO2xe2x80x94NR4xe2x80x94 in which the sulfonyl group is linked to xe2x80x94(CR1R2)pxe2x80x94 and R4 is as defined above;
(iii) xe2x80x94NR4xe2x80x94 in which R4 is as defined above;
(iv) xe2x80x94CHxe2x95x90Nxe2x80x94 in which the nitrogen atom is linked to A; and
(v) a hydrogen atom;
n represents 0 or 1; on the condition that xe2x80x94A(X)xe2x80x94(E)nxe2x80x94(CR1R2)pxe2x80x94Zxe2x80x94R3 does not represent halophenyl, methylphenyl, dichlorophenyl, dimethylphenyl, 4-ethoxy-2-methylaminophenyl, methylindolyl, dimethylindolyl, 2-hydroxyphenyl substituted with a group X, 2-methoxyphenyl substituted with a group X and optionally substituted 2-fluorophenyl as defined above, and on the condition that when A represents pyridyl, X represents methyl and n is equal to 1, E does not represent xe2x80x94NR4xe2x80x94, as well as their addition salts with pharmaceutically acceptable bases.
Among the preferred compounds of the invention, there may be mentioned:
(1) nitromethyl 2-trifluoromethoxyphenyl ketone;
(2) nitromethyl 2-cyanophenyl ketone;
(3) nitromethyl 2-ethylphenyl ketone;
(4) nitromethyl 2-trifluoromethylphenyl ketone;
(5) nitromethyl 2-ethoxyphenyl ketone;
(6) nitromethyl 2-isopropyloxyphenyl ketone;
(7) nitromethyl 2-methyl-1-naphthyl ketone;
(8) nitromethyl 3-chloro-2-naphthyl ketone;
(9) nitromethyl 3-chlorobenzo[b]thien-2-yl ketone;
(10) nitromethyl 6-methoxy-5-trifluoromethyl-1-naphthyl ketone;
(11) 4-methyl-N-[2-nitromethylcarbonyl-3-methyl-benzo[b]thien-5-yl]benzenesulfonamide;
(12) N-[3-chloro-4-nitromethylcarbonylphenyl]acetamide;
(13) nitromethyl 4-amino-2-chlorophenyl ketone;
(14) N-[3-chloro-4-nitromethylcarbonylphenyl]benzamide;
(15) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-chlorobenzamide;
(16) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-methylbenzamide;
(17) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-methoxybenzamide;
(18) N-[3-chloro-4-nitromethylcarbonylphenyl)-2-trifluoromethylbenzamide;
(19) N-[3-chloro-4-nitromethylcarbonylphenyl]-2,2,3,3-tetramethylcyclopropanecarboxamide;
(20) N-[3-chloro-4-nitromethylcarbonylphenyl]hexaneamide;
(21) N-[3-chloro-4-nitromethylcarbonylphenyl]cyclopentylacetamide;
(22) N-[3-chloro-4-nitromethylcarbonylphenyl]-3-phenylpropaneamide;
(23) N-[3-chloro-4-nitromethylcarbonylphenyl]-2-phenylpropaneamide;
(24) N-[3-chloro-4-nitromethylcarbonylphenyl]phenylacetamide;
(25) N-[3-chloro-4-nitromethylcarbonylphenyl]benzo[b]thienyl-2-carboxamide;
(26) N-[3-chloro-4-nitromethylcarbonylphenyl]benzofuryl-2-carboxamide;
(27) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-chlorophenoxyacetamide;
(28) 2-chloro-N-[3-chloro-4-nitromethylcarbonylphenyl]phenylacetamide;
(29) N-[3-chloro-4-nitromethylcarbonylphenyl]-1-(4-chlorophenyl)cyclopropylcarboxamide;
(30) N-[3-chloro-4-nitromethylcarbonylphenyl]-2-trifluoromethylphenylacetamide;
(31) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-chlorobenzenesulfonamide;
(32) N-[3-chloro-4-nitromethylcarbonylphenyl]benzenesulfonamide;
(33) nitromethyl 4-[N,N-di(phenylmethyl)amino]-2-chlorophenyl ketone;
(34) N-[2-chloro-3-nitromethylcarbonylphenyl]acetamide;
(35) N-[2-chloro-3-nitromethylcarbonylphenyl]-2-methylphenylacetamide;
(36) N-[4-chloro-3-nitromethylcarbonylphenyl]acetamide;
(37) N-[4-chloro-3-nitromethylcarbonylphenyl]-2-methylphenylacetamide;
(38) N-[4-chloro-3-nitromethylcarbonylphenyl]benzenesulfonamide;
(39) 2-[3-chloro-4-nitromethylcarbonylphenylaminocarbonyl-methylaminocarbonyl]benzoic acid;
(40) N-[3-chloro-4-nitromethylcarbonylphenyl]-1,3-di-hydro-1,3-dioxo-2H-isoindol-2-ylacetamide;
(41) 1-[3-chloro-4-nitromethylcarbonylphenyl]-3-phenylsulfonylurea;
(42) nitromethyl 3-methyl-2-thienyl ketone;
(43) N-[3-chloro-4-nitromethylcarbonylphenyl]-2-methylphenylacetamide;
(44) N-[3-chloro-4-nitromethylcarbonylphenyl]-2-oxo-piperidine;
(45) N-[3-chloro-4-nitromethylcarbonylphenyl]-1-(4-chlorophenyl)cyclopentanecarboxamide;
(46) N-[3-chloro-4-nitromethylcarbonylphenyl]indan-2-ylacetamide;
(47) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-chlorophenylacetamide;
(48) N-[3-chloro-4-nitromethylcarbonylphenyl]-3-chlorophenylacetamide;
(49) N-[3-chloro-4-nitromethylcarbonylphenyl]-3,4-di-chlorophenylacetamide;
(50) N-[3-chloro4-nitromethylcarbonylphenyl]-4-methylphenylacetamide;
(51) N-[3-chloro-4-nitromethylcarbonylphenyl]-3-methylphenylacetamide;
(52) N-[3-chloro-4-nitromethylcarbonylphenyl]-3,4-di-methylphenylacetamide;
(53) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-trifluoromethylphenylacetamide;
(54) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-methoxyphenylacetamide;
(55) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-nitrophenylacetamide;
(56) N-[3-chloro-4-nitromethylcarbonylphenyl]-2-fluorobromophenylacetamide;
(57) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-fluorophenylacetamide;
(58) N-[3-chloro-4-nitromethylcarbonylphenyl]-3-phenyl-2-propeneamide;
(59) N-[3-methyl-4-nitromethylcarbonylphenyl]-2-methylphenylacetamide;
(60) N-[2-bromo-4-nitromethylcarbonylphenyl]-2-methylphenylacetamide;
(61) nitromethyl 2-chloro-4-methoxyphenyl ketone;
(62) nitromethyl 2-isopropylphenyl ketone;
(63) N-[4-chloro-2-nitromethylcarbonylphenyl]-2-methylphenylacetamide;
(64) nitromethyl 2-chloro-4-phenylthiophenyl ketone;
(65) N-[3-chloro-4-nitromethylcarbonylphenyl]-4-[3-chloro-4-nitromethylcarbonylphenylaminocarbonyl]-3-phenylbutaneamide;
(66) nitromethyl 2-chloro-4-phenylsulfinylphenyl ketone;
(67) nitromethyl 4-chloro-2-trifluoromethoxyphenyl ketone;
(68) N-[2-(3-chloro-4-nitromethylcarbonylphenylethyl)]-2-methylbenzenesulfonamide;
(69) N-[3-bromo-4-nitromethylcarbonylphenyl]-2-methylphenylacetamide;
(70) N-(3-chloro-4-nitromethylcarbonylphenyl]-N-iso-propylbenzenesulfonamide.
The compounds of the invention are for example prepared according to the following methods (A) and (B):
(A) The products of formula (I) may be prepared from the carboxylic acids (II) 
by the action of di-(C1-C7)alkyl cyanophosphonate and nitromethane in the presence of a base in a solvent which is inert towards the reaction, preferably in a polar aprotic solvent such as dimethylformamide or tetrahydrofuran. Advantageously, the molar ratio of the carboxylic acid of formula (II) to the nitromethane varies between 0.6/1 and 2/1, preferably between 0.8/1 and 1.2/1. As base, use is preferably made of an amine, an alkyllithium, an alkali metal hydride, an alkali metal carbonate, an alkali metal hydroxide or an alkali metal alcoholate and especially triethylamine, pyridine, butyllithium, sodium hydride, potassium carbonate, potassium hydroxide or potassium tert-butoxide in a ratio of the carboxylic acid of formula (II) to the base of between 0.2/1 and 0.5/1, or better still in a ratio of 0.4/1.
The reaction temperature is generally between xe2x88x9278xc2x0 C. and the reflux temperature of the solvent and preferably between xe2x88x925xc2x0 C. and 80xc2x0 C. Generally, the reaction is continued for 2 to 72 hours, preferably for 2 to 18 hours.
(B) As a variant, the product of formula (I) may be prepared from the carboxylic acids of formula (II) by prior conversion to the phenyl ester of formula (III) according to the following reaction scheme: 
a) The preparation of the phenyl esters (III) may be carried out by reacting successively or simultaneously SOCl2, or POCl3, and phenol in the absence or in the presence of a solvent which is inert towards the reaction. When a solvent is used, it is preferably an aprotic solvent such as dichloromethane, benzene or toluene. In this first step, the molar ratio of SOCl2, respectively POCl3, to the carboxylic acid of formula (II) is preferably between 1/1 and 50/1, or better still the ratio is 10/1. Likewise, it is preferable that the molar ratio of the carboxylic acid to the phenol is between 1/0.9 and 1/1.2, or better still this ratio is 1/1.05. The reaction temperature is advantageously between xe2x88x9278xc2x0 C. and the reflux temperature of the solvent, preferably between 0xc2x0 C. and the reflux temperature of the solvent. This reaction is continued for 1 to 48 hours, preferably for 1 to 8 hours.
b) The phenyl esters of formula (III) thus formed are then treated with nitromethane in the presence of a base at a temperature of between 20xc2x0 C. and the boiling point of the solvent and, preferably, between 20xc2x0 C. and 40xc2x0 C. The duration of the reaction varies advantageously between 2 and 72 hours, preferably between 2 and 48 hours. For this stage, the molar ratio of the compound of formula (III) to the nitromethane will be set at between 1/1 and 1/5, this ratio being preferably equal to 1/3. As appropriate base, there will be used for example an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydride, an alkyllithium, an amine or an alkali metal alcoholate. Thus, the base may be, for example, selected from potassium tert-butoxide, sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydride, butyllithium and pyridine. The molar ratio of the phenyl ester of formula (III) to the base will be advantageously between 1/1 and 1/5, this ratio being preferably equal to 1/3.
Other procedures allow the preparation of the compounds of formula (I).
When in the formula (I) above, n is equal to 1 and E represents xe2x80x94COxe2x80x94NR4xe2x80x94, the compounds of the invention may be obtained by reacting an acid halide of formula R3xe2x80x94Zxe2x80x94(CR1R2)pxe2x80x94CO-hal where R1, R2, R3, Z and p are as defined above and hal is a halogen atom, with an amine of formula (IV): 
in which A and X are as defined above.
The procedure is carried out in the presence of a base, preferably an amine, such as pyridine, triethylamine or dimethylaminopyridine, in a solvent, preferably an aprotic solvent, at a temperature of between xe2x88x9220xc2x0 C. and the reflux temperature of the solvent, for example between 0 and 40xc2x0 C. The duration of the reaction is between 2 and 48 hours.
Examples of preferred solvents are dichloromethane, tetrahydrofuran, benzene or toluene.
When, in the formula (I) above, n is equal to 1 and E represents xe2x80x94SO2xe2x80x94NR4xe2x80x94, the compounds of the invention may be obtained by reacting a sulfonyl halide of formula R3xe2x80x94Zxe2x80x94(CR1R2)pxe2x80x94SO2-hal where R1, R2, R3, Z and p are as defined above and hal is a halogen atom, with an amine of formula (IV) as defined above. Here again, the procedure is advantageously carried out in the presence of a base in a solvent at a temperature of between xe2x88x9220xc2x0 C. and the reflux temperature of the solvent. The preferred operating conditions are the same as for the reaction of the acid chloride with the amine of formula (IV) above.
As a variant, it is possible, in a first instance, to synthesize the benzyl ester of formula (III): 
according to one of the reaction steps (i) to (vi) below, and then to treat the benzyl ester of formula (III) by the action of nitromethane in the presence of a base as described above:
step (i) when n is equal to 1 and E represents xe2x80x94COxe2x80x94NR4xe2x80x94, an acid halide of formula R3xe2x80x94Zxe2x80x94(CR1R2)pxe2x80x94CO-hal, where R1, R2, R3, Z and p are as defined above and hal is a halogen atom, is reacted with an amine of formula (V): 
xe2x80x83in which A and X are as defined above; or
step (ii) when n is equal to 1 and E represents xe2x80x94SO2xe2x80x94NR4xe2x80x94, a sulfonyl halide of formula R3xe2x80x94Zxe2x80x94(CR1R2)pxe2x80x94SO2-hal, where R1, R2, R3, Z and p are as defined above and hal is a halogen atom, is reacted with an amine of formula (V) as defined above; or
step (iii) when n is equal to 1 and E represents xe2x80x94NR4xe2x80x94, a compound of formula R3xe2x80x94Zxe2x80x94(CR1R2)p-hal, where R1, R2, R3, Z and p are as defined above and hal is a halogen atom, is reacted with an amine of formula (V) as defined above; or
step (iv) when n is equal to 1 and E represents xe2x80x94CHxe2x95x90Nxe2x80x94, an aldehyde of formula R3xe2x80x94Zxe2x80x94(CR1R2)pxe2x80x94CHO, where R1, R2, R3, Z and p are as defined above, is reacted with an amine of formula (V) as defined above; or
step (v) when n is equal to 1 and E represents xe2x80x94Oxe2x80x94, a compound of formula R3xe2x80x94Zxe2x80x94(CR1R2)p-hal, where R1, R2, R3, Z and p are as defined above and hal is a halogen atom, is reacted with an alcohol of formula (VI): 
xe2x80x83in which A and X are as defined above;
step (vi) when n is equal to 1, E represents xe2x80x94COxe2x80x94NR4xe2x80x94, p is 0 and Z represents xe2x80x94SO2xe2x80x94NHxe2x80x94, an isocyanate of formula R3xe2x80x94SO2xe2x80x94Nxe2x95x90Cxe2x95x90O, in which R3 is as defined above, is reacted with an amine of formula (V) as defined above;,
step (vii) when n is equal to 1 and E represents xe2x80x94COxe2x80x94NR4xe2x80x94, an acid of formula R3xe2x80x94Zxe2x80x94(CR1R2)pxe2x80x94COOH, where R1, R2, R3, Z and p are as defined above, is reacted with an amine of formula (V) as defined above.
Some compounds of formula (I) may be obtained from compounds of formula (I) using simple conversion steps.
Thus, the compounds of formula (I) in which n is equal to 1, E represents xe2x80x94COxe2x80x94NHxe2x80x94, p represents 1, R1 and R2 represent a hydrogen atom, Z represents a bond and R3 represents 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl may be prepared from the corresponding compounds (having meanings of A and X which are identical) in which n is equal to 1, E represents xe2x80x94COxe2x80x94NHxe2x80x94, p represents 1, R1 and. R2 represent a hydrogen atom, Z represents xe2x80x94COxe2x80x94NHxe2x80x94 and R3 represents 2-carboxyphenyl, by the action of hydrochloric acid.
Likewise, the compounds in which n represents 1, E represents xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94(CR1R2)pxe2x80x94 represents CH2 and R3 represents 2-((4-nitromethylcarbonyl-3-chlorophenyl)-aminocarbonyl]-1-(phenyl)ethyl may be prepared by reacting the dichloride of formula
Clxe2x80x94COxe2x80x94CH2xe2x80x94CH(C6H5)xe2x80x94CH2xe2x80x94COxe2x80x94Cl
xe2x80x83with two equivalents of the ester of formula
NH2xe2x80x94A(X)xe2x80x94COOC6H5 
xe2x80x83in the presence of a base, and then treating the compound obtained with nitromethane in the presence of a base.
The compounds of formula (IV) are easily synthesized from commercially available compounds by methods known in the art.
By way of example, the compounds of formula (IV) may be obtained from the corresponding amines of formula (VII):
NH2xe2x80x94A(X)COOPhxe2x80x83xe2x80x83(VII)
according to a procedure comprising the steps consisting of:
protecting the amino function with a protective group such as a (C1-C7)alkylcarbonyl group, for example acetyl;
reacting the amine thus protected with di (C1-C7) alkyl cyanoqphosphonate and nitromethane in the presence of a base; and then
deprotecting the amino function, for example by the action of sodium hydroxide when the protective group is an acetyl group.
The capacity of the compounds of the invention to inhibit the enzyme aldose reductase and to prevent the accumulation of sorbitol may be demonstrated during standard laboratory tests below:
1) Study in Vitro: Inhibition of Aldose Reductase
The aldose reductase used is obtained from male Wistar rat crystalline lenses according to a modification of the method of S. HAYMAN et al. (Journal of Biological Chemistry 240, p., 877, 1965). The enzymatic extract is diluted in a phosphate buffer in the presence of NADPH and various concentrations of the test products. The reaction is initiated, with L-glyceraldehyde and the reaction rate is measured by monitoring the disappearance of NADPH by spectrophotometry at 340 nm. The reaction rate is calculated for each product concentration and then the concentration necessary for a 50% reduction in the reaction rate (IC50) is evaluated by linear interpolation. The results are presented in Table 1 below.
2) Study in Vivo: Reduction of Sorbitol Accumulation
200 to 250 g male Wistar rats are made diabetic by intravenous injection of streptozotocin (60 mg/kg). They then receive an oral treatment of the test products, in the form of a suspension, 4 hours, 30 hours and 52 hours after the injection of streptozotocin. Eighteen hours after the last oral treatment, the rats are stunned and decapitated and then their sciatic nerves are removed. After extraction, the sorbitol level in the nerves is measured according to the enzymatic method described by H. U. BERGMEYER (Methods of enzymatic analysis. H. U. BERGMEYER ed., Academic Press New York 3, p. 1323, 1974).
The percentage protection is calculated for each product relative to the batch of diabetic animals taking into account the sorbitol level in the sciatic nerves of nondiabetic rats.
By way of example, the results obtained for some of the test products are given in the following table:
The compounds of the invention may be used by way of medicaments as aldose reductase inhibitors, and are especially useful in the treatment of the complications of diabetes such as cataracts, retinopathies, neuropathies, nephropathies and certain vascular diseases. The daily dosages may vary from 5 mg to 200 mg of active ingredient, for example.
These medicaments may be administered by the oral route in the form of tablets, gelatin capsules or granules affording immediate release or controlled release, by the intravenous route in the form of an injectable solution, by the transdermal route in the form of an adhesive transdermal device, by the local route in the form of a collyrium, solution, cream or gel.
A solid medicament for oral administration containing a compound of the present invention, as active ingredient is prepared by supplementing the said compound with a filler and, where appropriate, a binder, a disintegrating agent, a lubricant, a coloring or a taste enhancer, and by forming the mixture into a tablet, a coated tablet, a granule, a powder or a capsule.
Examples of, a filler comprise lactose, maize starch, sucrose, glucose, sorbitol crystalline cellulose and silicon dioxide, and examples of a binder comprise poly(vinyl alcohol), poly(vinyl ether), ethyl cellulose, methyl cellulose, acacia, tragacanth gum, gelatin, shellac, hydroxypropylcellulose, hydroxypropylmethylcellulose, calcium citrate, dextrin and pectin. Examples of lubricants comprise magnesium stearate, talc, poyethylene glycol, silica and hardened vegetable oils. The coloring may be any of those permitted for use in medicaments. Examples of taste enhancers comprise cocoa powder, mint in herb form, aromatic powder, mint in oil form, borneol and cinnamon powder. Of course, the tablet or granule may be suitably coated with sugar, gelatin and the like.
An injectable form containing the compound of the present invention as active ingredient is prepared, where appropriate, by mixing the said compound with a pH regulator, a buffering agent, a suspending agent, a solubilizing agent, a stabilizer, a tonic agent and/or a preservative, and by converting the mixture to a form injectable by the intravenous, subcutaneous or intramuscular route, according to a conventional process. Where appropriate, the injectable form obtained may be freeze-dried by a conventional process.
Examples of suspending agents comprise methyl cellulose, polysorbate 80, hydroxyethylcellulose, acacia, tragacanth gum powder, sodium carboxymethylcellulose and polyethoxylated sorbitan monolaurate.
Examples of a solubilizing agent comprise castor oil solidified with polyoxyethylene, polysorbate 80, nicotinamide, polyethoxylated sorbitan monolaurate and the ethyl ester of castor oil fatty acid.
In addition, the stabilizer comprises sodium sulfite, sodium metasulfite and ether, whereas the preservative comprises methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol.
A few pharmaceutical formulations are given below by way of nonlimiting examples: